EP1569636B1 - Utilisation d'equol dans le traitement de maladies d'origine androgenique - Google Patents

Utilisation d'equol dans le traitement de maladies d'origine androgenique Download PDF

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EP1569636B1
EP1569636B1 EP03777994.9A EP03777994A EP1569636B1 EP 1569636 B1 EP1569636 B1 EP 1569636B1 EP 03777994 A EP03777994 A EP 03777994A EP 1569636 B1 EP1569636 B1 EP 1569636B1
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equol
phyto
dht
fed
rats
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EP1569636A4 (fr
EP1569636A2 (fr
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Edwin Douglas Lephart
Trent D. Lund
Kenneth David Reginald Setchell
Robert J. Handa
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Cincinnati Childrens Hospital Medical Center
Brigham Young University
Colorado State University Research Foundation
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Cincinnati Childrens Hospital Medical Center
Brigham Young University
Colorado State University Research Foundation
Colorado State University
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Definitions

  • This invention relates equol and its mechanism of action and use as a therapeutic compound for treating and preventing physiological and pathophysiological conditions mediated by androgens.
  • phytoestrogens have received increased investigative attention due to their potential protective effects against age-related diseases (e.g. cardiovascular disease and osteoporosis) and hormone-dependent cancers (i.e., breast and prostate cancer).
  • age-related diseases e.g. cardiovascular disease and osteoporosis
  • hormone-dependent cancers i.e., breast and prostate cancer.
  • isoflavones derived principally from soybeans
  • lignans found in flaxseed in large quantities
  • coumestans derived from sprouting plants like alfalfa
  • human consumption of isoflavones has the largest impact due to its availability and variety in food products containing soy.
  • genistin the precursor of genistein
  • glycosidic form that contains a carbohydrate portion of the molecule.
  • malonylglucoside and acetylglucoside forms also are found.
  • These conjugates are metabolized in the GI tract by intestinal bacteria, which hydrolyze the carbohydrate moiety to the biologically active phytoestrogen, genistein.
  • the same metabolic step occurs for the aglycone daidzein, which is converted from the glycosidic form daidzin.
  • Diadzein is then further metabolized to equol in an "equol-producing" mammal. Thereafter, equol circulates in the blood stream at very high concentrations.
  • Equol is not normally present in the urine of most healthy adults unless soy is consumed.
  • the formation of equol in vivo is exclusively dependent on intestinal microflora as evidenced from the finding that germ-Phyto-Free animals do not excrete equol, and that equol is not found in the plasma and urine of newborn or 4-month old infants fed exclusively soy foods from birth due to the fat that the intestinal flora has not yet developed in neonates. See Setchell K.D.R. et al The Lancet 1997; 350:23-27 .).
  • the phenolic ring structures of isoflavones enable these compounds to bind estrogen receptors (ER) and mimic estrogen. Although genistein and daidzein bind to ER, it is with a lower affinity when compared to estradiol, and with a greater affinity for ER ⁇ than to ER ⁇ . Additionally, phytoestrogens have been reported to act like natural selective estrogen receptor modulators (SERMs) at various tissue sites throughout the body. In some tissues, there is evidence that phytoestrogens act as estrogen agonists, whereas in others, they display antagonistic characteristics comparable to that of tamoxifen or raloxifene where SERM activity appears to be sex-hormone and gender dependent.
  • SERMs selective estrogen receptor modulators
  • Equol (7-hydroxy-3(4'hydroxyphenyl)-chroman) represents the major metabolite of the phytoestrogen daidzein, one of the main isoflavones found abundantly in soybeans and soy-foods. Equol, however, is not a phytoestrogen, because it is not a natural constituent of plants. Equol does not occur naturally in any plant-based products. Rather, it is a non-steroidal isoflavone that is exclusively a product of intestinal bacterial metabolism (relatively few individuals, ⁇ 30-40%, have the micro flora necessary to convert soy isoflavones to equol).
  • equol possess some weak estrogenic properties, binds sex hormone binding globulin, binds ⁇ -fetoprotein, and has antioxidant activity.
  • equol is unique among the plant-derived isoflavones in that it possesses a chiral center and as such exists as two distinct enantiomeric forms, the R- and S- enantiomers.
  • the S-enantiomer of equol is the exclusive equol form found in the urine and plasma of "equol-producing" mammals consuming soy, and is the only equol enantiomer made by human intestinal bacteria.
  • the prostate gland depends on androgen hormone action for its development and growth, and the development of human benign prostatic hyperplasia (BPH) clearly requires a combination of testicular androgens during the aging process.
  • testosterone is not the major androgen responsible for growth of the prostate.
  • the principal prostatic androgen is dihydrotestosterone (DHT), as evidenced by current treatments of prostatic cancer are directed toward reducing DHT with 5 ⁇ -reductase inhibitors.
  • DHT levels in the prostate remain at a normal level with aging, despite a decrease in the plasma testosterone.
  • Testosterone is converted to DHT by 5 ⁇ -reductase in prostatic stromal and basal cells.
  • DHT is primarily responsible for prostate development and the pathogenesis of BPH.
  • Inhibitors of 5 ⁇ -reductase reduce prostate size by 20% to 30%. This reduction in glandular tissue is achieved by the induction of apoptosis, which is histologically manifested by ductal atrophy.
  • 5 ⁇ -reductase occurs as 2 isoforms, type 1 and type 2, with the prostate expressing predominantly the type-2 isoform, and the liver and skin expressing primarily the type-1 isoform. Patients have been identified with deficiencies in the type-2 5 ⁇ -reductase, but not type 1.
  • Knockout mice with the type-2 5 ⁇ -reductase null-mutation demonstrate a phenotype similar to that seen in men with 5 ⁇ -reductase deficiency.
  • Type-1 5 ⁇ -reductase knockout male mice are phenotypically normal with respect to reproductive function. Enzymatic activity for 5 ⁇ -reductase or immunohistochemical detection has been noted in other genitourinary tissues, such as the epididymis, testes, gubernaculum, and corporal cavernosal tissue.
  • DHEAS dehydroepiandrosterone sulphate
  • DHEA dehydroepiandrosterone
  • A testosterone
  • T testosterone
  • DHT DHT in descending order of serum concentration, though only the latter two bind the androgen receptor to a significant degree.
  • the other three steroids are better considered as pro-androgens.
  • -DHT is primarily a peripheral product of testosterone metabolism.
  • Testosterone circulates both in its free form, and bound to protein including albumin and sex steroid hormone-binding globulin (SHBG), the levels of which are an important determinant of free testosterone concentration.
  • SHBG albumin and sex steroid hormone-binding globulin
  • Widyarini et al. (2001) Photochemistry and Photobiology Vol 74 pages 465-470 discusses how isoflavonoid compounds including equol from Red Clover protect from inflammation and immune suppression induced by UV radiation.
  • Lephart et al (2001) Neuroreport Vol 12, pages 3451-3455 discloses dietary soy phytoestrogen effects on brain structure and aromatase in Long-Evans rats.
  • the present disclosure relates to a method of modulating physiological and pathophysiological conditions mediated by androgens in a mammal, comprising the step of administering to the mammal an effective amount of an enantiomeric equol that can bind with free 5 ⁇ -dihydrotestosterone, thereby inhibiting the binding of 5 -dihydrotestosterone with the androgen receptors (AR) in the mammal and mediating the conditions mediated by the androgen.
  • AR androgen receptors
  • the present disclosure also relates to a method of treating and preventing an androgen-related disease in a mammal, comprising the step of administering to the mammal an effective amount of an enantiomeric equol that can bind with free 5 ⁇ -dihydrotestosterone, thereby inhibiting the binding of the 5 ⁇ -dihydrotestosterone with the androgen receptors in the mammal.
  • the present disclosure further relates to a method of modulating androgen hormone activity in a mammal, comprising the step of administering to the mammal an effective amount of an enantiomeric equol that can bind with free 5 ⁇ -dihydrotestosterone, thereby modulating the binding of 5 ⁇ -dihydrotestosterone with the androgen receptors in the mammal.
  • the present disclosure additionally relates to a method of preventing DHT binding to the AR by contacting the DHT with an enantiomeric equol prior to the binding of DHT and AR.
  • the present disclosure relates to a method of treating and preventing a combination of an androgen-related condition and an estrogen-related condition in a mammal, comprising the step of administering to a mammal an effective amount of a mixture of R-equol and S-equol, that can bind with free 5 ⁇ -dihydrotestosterone, and with free 5 ⁇ -dihydrotestosterone and the estrogen receptor, respectively, thereby inhibiting the binding of the 5 ⁇ -dihydrotestosterone with the androgen receptors, and affecting binding of the estrogen receptors.
  • the present disclosure also relates to a method of modulating age- related androgen/estrogen hormonal balances, comprising the steps of: 1) determining a mammal's endocrine androgen/estrogen hormone balance, 2) administering to the mammal an effective amount of a mixture of R-equol and S-equol, that can modulate the hormone balance of 5 ⁇ -dihydrotestosterone and estrogen.
  • the present disclosure further relates to a use of an enantiomeric equol to bind in vivo free DHT, for modulating physiological and pathophysiological conditions mediated by androgens in a mammal.
  • the present disclosure also relates to a method of regulating the level of LH in vivo in a mammal by contacting the DHT of the mammal with enantiomeric equol.
  • the present disclosure relates to a use of enantiomeric equol as a diagnostic agent for physiological and pathophysiological conditions mediated by androgens/androgen-related disorders affected by an estrogenic/androgenic imbalance.
  • the present invention describes the use of an R-equol enantiomer or a non-racemic mixture of R-equol and S-equol enantiomers at a ratio of S-equol to R-equol from less than 50:50 to 1:99.5 on the manufacture of a medicament for the treatment of a pathophysiological condition mediated by androgens in a mammal, wherein said pathophysiological condition is selected from obesity or body weight gain.
  • the present invention provides an R-equol enantiomer or a non-racemic mixture of R-equol and S-equol enantiomers at a ratio of S-equol to R-equol from less than 50:50 to 1:99.5 for use in a method of treating a pathophysiological condition mediated by androgens in a mammal, wherein said pathophysiological condition is selected from obesity or body weight gain.
  • the present invention also provides a competitive binding assay for determining the presence of an androgen binding moiety, disclaiming diagnostic methods practised on the human or animal body, said assay comprising the steps of:
  • Equol can act as an anti-androgen.
  • the anti-androgenic properties of equol are unique in that equol does not bind the androgen receptor (AR) but specifically binds 5 ⁇ -dihydrotestosterone (DHT) with high affinity and thereby prevents DHT from binding the AR
  • both the R- and S-enantiomers of equol specifically bind DHT, sequester DHT from the AR and block DHT's actions in physiological processes in vivo. Racemic equol, which constitutes R-equol and S-equol and R-equol or S-equol alone, selectively bind DHT.
  • DHT DHT
  • the AR which is encoded by a single-copy gene located on the human X-chromosome, specifically mediates the actions of androgens.
  • testosterone and DHT bind the AR, certain tissues (i.e. prostate gland, hair follicles, etc.) that are only slightly influenced by testosterone are greatly influenced by DHT.
  • DHT has been implicated in a number of diseases and disorders. Because equol specifically binds and prevents the actions of DHT, there is an indication for a broad and important usage for equol in the treatment of androgen-mediated pathologies.
  • Equol has a structure similar to the steroidal estrogen estradiol. Equol is unique among the isoflavones in that it possesses a chiral center and as such exists as two distinct enantiomeric forms, the R- and S- enantiomers. All previous studies on equol appear to have been conducted with the racemic form of equol. There has in general been a lack of appreciation that two forms of equol exist and to our knowledge no previous study has reported on the specific actions or activity of the individual enantiomers. R- and S-equol specifically bind 5 ⁇ -dihydrotestone (DHT). Equol racemic, R-equol or S-equol does not bind the androgen receptor.
  • DHT 5 ⁇ -dihydrotestone
  • R-equol does not bind the estrogen receptor system. S-equol only binds ER ⁇ (with an affinity approximately 5-times less than 17 ⁇ -estradiol). Thus, R- and S-equol have SERM-like properties along with having the capability to selectively bind the most potent circulating androgen, DHT.
  • Such effects open up novel possibilities for dietary, nutraceutical, and pharmacological approaches to prevention and treatment of disease where the potent androgen DHT plays a detrimental role.
  • the estrogenic actions of S-equol can also be of benefit in treating or preventing prostate cancer because the combined actions of equol acting at the estrogen receptor level and as an antiandrogen.
  • Equol (7-hydroxy-3(4'hydroxyphenyl)-chroman) represents the major metabolite of phytoestrogens daidzin and daidzein, isoflavones found abundantly in soybeans and soy-foods, and is an important biologically active molecule.
  • the major circulating isoflavone is equol, which accounts for 70-90% of the total circulating isoflavone levels.
  • the present disclosure discloses a novel model of equol's biological properties. In binding studies, equol enantiomers specifically bind 5 ⁇ -dihydrotestosterone (DHT), but not testosterone, DHEA or estrogen.
  • DHT 5 ⁇ -dihydrotestosterone
  • equol can act as an anti-androgen, by specifically binding DHT and preventing DHT from binding to the androgen receptor (AR) without itself binding the AR. It also has been shown that DHT that has already been bound to the AR will not be competitively bound by enantiomeric equol.
  • one embodiment of the present disclosure is a method of preventing DHT binding to the AR by contacting DHT with equol prior to DHT-AR binding occurs.
  • the enantiomeric equol may be brought into contact with the DHT in vitro or in vivo.
  • the equol may be administered by any route that allows absorption of equol to the blood stream.
  • Biologically available DHT is free and unbound by any native ligand prior to binding with equol.
  • the ratios are still significantly different between equol-treated and control values. Equol also blocked DHT's androgenic trophic influence on the prostate and epididymis, without significantly altering testosterone levels.
  • DHT has negative feedback effects on circulating plasma levels of luteinizing hormone (ILH). Equol significantly increases LH levels by binding DHT and preventing this feedback effect. Equol completely reverses the inhibitory action of DHT on LH levels in gonadectomized (GDX) males, whereas DHT plus equol- treated male rats display LH levels similar to that of control values.
  • GDX gonadectomized
  • an embodiment of the present disclosure is a method of modulating LH levels in an individual by contacting the DHT of the individual with enantiomeric equol.
  • the equol can be administered by any route that allows absorption of equol to the blood stream, with the amount administered in accordance with the nature of the ailment to be treated and size of the individual.
  • Equol is distinct from most isoflavones in having a chiral center due to the lack of a double bond in the heterocyclic ring.
  • the phytoestrogen isoflavones from soy do not have a chiral center.
  • FIGURE 1 shows the chemical structures of R-equol and S-equol.
  • the R- and S- enantiomers conformationally differ and this is predicted to influence how an equol enantiomer fits into the binding site in the cavity of the dimerized ER complex, and how it binds with DHT.
  • the present disclosure includes a composition having an at least physiological acceptable quantity of equol that is able to bind and sequester free DHT (but not testosterone or DHEA) thereby preventing it binding to the androgen receptor following administration to an individual thereby having important ramifications in health and disease and a broad and important use in the treatment of androgen- mediated pathologies.
  • a composition containing S-equol, R-equol, a racemic equol mixture, or a non-racemic equol mixture can be made for oral consumption.
  • the composition or a product containing the composition can be a marketed or institutional food product, a pharmaceutical, and an OTC medicament.
  • a food composition can comprise at least 1 mg, and typically up to 200 mg, enantiomeric equol or equol mixtures, per serving.
  • An orally-administered medicament can comprise at least 1 mg, and typically up to 200 mg, enantiomeric equol or equol mixture, per dose.
  • a product for topical application can comprise at least 0.1%, and up to 10%, by weight S-equol, or R-equol, or enantiomeric mixtures.
  • a topical composition of the present invention can include other cosmetic and pharmaceutical actives and excipients.
  • suitable cosmetic and pharmaceutical agents include, but are not limited to, antifungals, vitamins, anti-inflammatory agents, antimicrobials, analgesics, nitric oxide synthase inhibitors, insect repellents, self-tanning agents, surfactants, moisturizers, stabilizers, preservatives, antiseptics, thickeners, lubricants, humectants, chelating agents, skin penetration enhancers, emollients, fragrances and colorants.
  • An enantiomeric equol can also be an enantiomeric equol conjugate, conjugated at the C-4' or the C-7 position with a conjugate selected from the group consisting of glucuronide, sulfate, acetate, propionate, glucoside, acetyl-glucoside, malonyl-glucoside, and mixtures thereof.
  • a composition or preparation comprising enantiomeric or mixture of equol, for administering to subjects for the treatment and/or prevention of, or for reducing the predisposition to, androgen-related diseases and conditions related thereto can also comprise one or more pharmaceutically acceptable adjuvants, carriers and/or excipients.
  • Pharmaceutically acceptable adjuvants, carriers and/or excipients are well known in the art, for example as described in the Handbook of Pharmaceutical Excipients, second edition, American Pharmaceutical Association, 1994 .
  • the composition can be administered in the form of tablets, capsules, powders for reconstitution, syrups, food (such as food bars, biscuits, snack foods and other standard food forms well known in the art), or in drink formulations. Drinks can contain flavoring, buffers and the like.
  • the composition of the invention can comprise a non-racemic mixture of S-equol and R-equol, having an EE for S-equol of more than 0% and less than 90%.
  • a composition that has an EE of 0% is a 50:50 racemic mixture of the two enantiomers.
  • the composition can be made directly from a racemic mixture, by an incomplete separation and removal of either the R-equol or S-equol enantiomer from the racemic mixture.
  • the composition can also be made by combining a first equol component comprising a mixture (either a non-racemic or racemic mixture) of equol, with a second component comprising a composition consisting essentially of S-equol or R-equol.
  • a composition can be prepared comprising S-equol and R-equol at a ratio of S-equol to R-equol from greater than about 50:50 to about 99.5:1, more typically about 51:49 to about 99:1, and from less than about 50:50 to about 1:99.5, more typically about 49:51 to about 1:99.
  • compositions suitable for oral administration can be presented in discrete units, such as capsules, cachets, lozenges, or tablets, each containing a predetermined amount of the extract; as a powder or granules; as a solution or a suspension in an aqueous or non-aqueous liquid; or as an oil-in-water or water-in-oil emulsion.
  • composition typically does not comprise a significant amount of any other androgen-receptor binding compound.
  • Equol is formed following the hydrolysis of the glycoside conjugates of daidzein from soy, and the methoxylated isoflavone formononetin, or its glycosidic conjugates found in clover. Once formed, equol appears to be metabolically inert, undergoing no further biotransformation, save phase II metabolism or a minor degree of additional hydroxylation in the liver. As with daidzein and genistein, the predominant phase II reactions are glucuronidation and, to a minor extent, sulfation.
  • Cut-off values have been empirically derived permitting assignment of individuals to either of these categories. People who have plasma equol concentrations of less than 10 ng/mL (40 nmol/L) can be classified as 'non-equol producers' and where levels are above 10 ng/mL (40 nmol/L) this defines 'equol producers'. This distinction can also be derived from the levels in urine, an equol producer being someone excreting greater than 1000 nmol/L. Although the excretion of equol is highly variable among individuals there is a large demarcation between those that can produce equol and those that cannot, consistent with a precursor-product relationship in enzyme kinetics catalyzing the reaction. There is consequently an inverse relationship between urinary daidzein and equol levels, and thus far no significant gender differences have been defined.
  • Enantiomeric equol can be prepared per se or as the racemic mixture.
  • Chemical synthesis routes can be used to produce the racemic mixture in good yields. In a typical synthesis process, standard chemical treatments are used to hydrogenate the double-bond of the heterocyclic ring and to remove the carbonyl at position C-3.
  • Typical starting materials are isoflavones such as daidzein, genistein, glycitein, horrarin, formononetin and biochanin A and their glucoside conjugates. Any conjugated form would be reduced to its aglycon by hydrolysis.
  • Suitable solvents for the reaction include organic acids such as glacial acetic acid, lower alcohols such as isopropanol, and mixtures thereof.
  • Reduction catalysts typically employed include Palladium, such as 10% Pd on charcoal. Reactions can run at temperatures from ambient to 60 °C, with pressures ranging from slightly above ambient, up to 200 psig (14 atm. gauge), and with reaction times of up to 30 hours or more.
  • the catalyst is removed and any filtrate evaporated.
  • the crude residue is purified, typically by chromatography employing a silica gel column, with an eluent comprising C2-C4 alcohols, C3-C7 alkanes, and mixtures thereof
  • the purified residue can be crystallized from n-hexane to produce ( ⁇ )equol as a pure product, typically of at least 99%, with a yield typically of at least 75%.
  • the equol crystallized product is colorless, not hygroscopic, and stable in air, and does not decompose during the final filtration procedure.
  • a racemic mixture of equol can be separated into its two distinct enantiomers using a chiral-phase column with a mobile phase comprising a C4-C8 alkyl and a C2-C4 alcohol.
  • a typical example of a chiral-phase column is a Chiralcel OD column or OJ column, supplied by Daicel Chemical Industries Ltd.
  • a preferred example of a mobile phase comprises 70% hexane and 30% ethanol.
  • the first eluent is typically S-equol. After a second period of time from passing the racemic mixture into the inlet, the second eluent R-equol is obtained.
  • the elution of an equol enantiomer from the column can be detected by UV absorbance at 260 - 280 nm or by a more specific detection system such as a mass spectrometer and monitoring of ions specific to equol.
  • S-equol can be produced biologically in bulk using conventional food technology.
  • a base solution media, food product or plant extract can be provided that comprises daidzein or another related isoflavone from which daidzein can be derived.
  • the daidzein or other isoflavone can be converted to S-equol by a standard bacterial or enzyme fermentation process, to provide a bulk solution, food product or plant extract that comprises S-equol.
  • Conversion of daidzein to equol involves three major steps: 1) hydrolysis of any glucoside conjugate group, 2) conversion of the isoflavone aglycons to a dihydro-intermediate, and 3) conversion of the dihydro- intermediate to equol.
  • the metabolic pathway and enzymes for each of the three steps required may not necessarily be present in one bacterium.
  • Anecdotal evidence from human studies suggests that there may be one or more bacteria that act in conjunction to perform these reactions, as evidenced from the fact that often dihydrodaidzein can be present in significant amounts in plasma and urine yet equol may be low or barely detectable.
  • equol may be produced from daidzein by a single organism it is believed that better or more efficient conversion can be achieved when using a mixture of bacterial species, each with its own metabolic profile.
  • Important conditions for effective conversion to S-equol include the selection of the bacterial organism or mixture of organisms, the temperature of incubation, and the amount of oxygen available to the organisms. These conditions can be optimized by techniques well known to persons skilled in this art. The organisms used to effect this change can be inactivated by standard techniques used in the food industry or, alternately, allowed to remain in an active state in the product.
  • one or more bacterial strains are required to convert the daidzein (or other related isoflavone) through intermediate products to S-equol, which generally involves one or more of the three major reactions: the conversion of isoflavone glycone to aglycon isoflavone; the conversion of aglycon isoflavone to dihydro isoflavone; and the conversion of dihydro isoflavone to the product, equol.
  • a mixed culture of organisms isolated from equine feces or a mixed culture of organisms derived from the gastrointestinal tract of a person known to an 'equol producer' can convert, as they do in vivo, the glycone daidzein to the final product S-equol.
  • Typical bacterial strains that can convert a glycone to an aglycon include Enterococcus faecalis, a Lactobacillus plantarum, Listeria welshimeri, a mixed culture of organisms isolated from the intestinal tract of an 'equol producing' mammal, Bacteriodes fragilis, Bifidobacterium lactis, Eubactria limosum, Lactobacillus casei, Lactobacillus acidophilous, Lactobacillus delbrueckii, Lactobacillus paracasei, Listeria monocytogenes, Micrococcus luteus, Proprionobacterium freudenreichii and Sacharomyces boulardii, and mixtures thereof.
  • Typical bacterial strains that can convert an aglycon to equol include Proprionobacteria freundenreichii, a mixed culture containing: Bifidobacterium lactis, Lactobacillus acidophilus, Lactococcus lactis, Enterococcus faecium, Lactobacillus casei and Lactobacillus salivarius; and a mixed culture of organisms isolated from the intestinal tract of an 'equol producing' mammal.
  • the time required for bacterial conversion of the glucosides to aglycons, or the aglycons to the equol product will depend upon bacteria-related factors, particularly concentration, the availability of oxygen, and the temperature and pH of the incubating system. In most instances it is possible to achieve substantially complete conversion within 24 hours.
  • the pH range for bacterial conversion of the isoflavone glucosides to aglycon isoflavones is from about 3 to about 9. The optimum pH depends primarily upon the type of bacteria used, and should be selected accordingly.
  • the time required for enzymatic conversion of the glucosides to aglycons, and aglycons to the equol product depends upon enzyme-related factors, particularly concentration, and the temperature and pH of the system. In most instances it is possible to achieve substantially complete conversion within 24 hours, more preferably within about 2 hours, and most preferably within about 1 hour.
  • S-equol produced in bulk can be separated from the resulting bulk solution of a bacterial production of S-equol, by methods well known in the art, including crystallization, solvent extraction, distillation, and precipitation/filtration.
  • the resulting bulk solution can contain unreacted daidzein or other related isoflavone used, by-products, and any reactants.
  • Such methods can include the use of a reverse-phase or straight-phase liquid chromatography column and these can be combined with chiral-phase chromatography
  • a typical method of removing S-equol from a bulk solution or solid phase is by extraction.
  • An extractant solution is added to the solution or solid phase containing the S-equol.
  • the extractant is a low molecular weight alcohol such as methanol, ethanol, isopropyl alcohol, or propyl alcohol, or an aqueous solution having a pH in the range from 3.5 to 5.5.
  • sufficient alcohol is added to bring the alcohol/water ratio to between a minimum of 40:60 and a maximum of 95:5. More typically, the ratio is at least 60:40, and even more typically a ratio between 65:35 and 90:10.
  • an aqueous acid solution is prepared with the pH adjusted to about 3.5 to about 5.5, and more preferably within the pH range of about 4.0 to about 5.0. Sufficient water is added to make a dilute liquid with a sufficiently low viscosity to permit separation of solids from liquids by centrifugation or filtration.
  • the liquid, from which insoluble solid matter has been removed, is concentrated by conventional methods for removing liquids. Methods used typically include, but are not limited to, removal of solvent by evaporation, preferably under reduced pressure.
  • the residual liquid is concentrated to at least about 15% solids, and up to about 55% solids, more typically to between 30% and 50% solids.
  • the concentrate is then diluted with water to reduce the solids content and increase the water to alcohol ratio.
  • the amount of water added can be varied over a wide range, though a final solids content between 6% and 15%, and more typically about 13%, is preferred.
  • the pH of the mixture is adjusted between about pH 3.0 and about pH 6.5, with a preferred value between about pH 4.0 and about pH 5.0.
  • the temperature is between about 2°C to about 10°C, and more typically about 5°C to 7°C.
  • the solid material is then separated from the liquid by standard separation techniques (centrifugation or filtration) and yields an equol-rich solid material.
  • the equol-rich material can optionally be purified, typically by chromatography employing a silica gel column, with an eluent comprising C2-C4 alcohols, C3-C7 alkanes, and mixtures thereof.
  • the purified residue can be crystallized from n-hexane to produce S-equol as a pure product, typically of at least 99%, with a yield typically of at least 75%.
  • the equol crystallized product is colorless, not hygroscopic, and stable in air, and does not decompose during the final filtration procedure.
  • the S-equol product can be authenticated by GC-MS analysis of the trimethylsilyl ether or tert-butyldimethylsilyl ether derivative, or some other appropriate volatile derivative of synthesized product as a single pure peak and a mass spectrum that is consistent with the published electron ionization spectrum of the trimethylsilyl (TMS) ether derivative of authentic equol. Confirmation of the product can also be established by direct mass spectrometry using electrospray ionization after introducing the sample into the instrument via an HPLC chiral-phase column.
  • This present disclosure provides a means for an individual subject to overcome the problem of not being able to produce equol in vivo, or to supply R-equol in particular, by providing delivery of equol enantiomers, the S-equol or R-equol, or non-racemic mixtures of S-equol and R-equol directly, circumventing the need for intestinal bacteria for its production or for the need to consume soy foods with equol's precursor isoflavones.
  • the delivery of S-equol can also supplement the in vivo production of S-equol in 'equol-producers', as well as in 'non-equol producers'.
  • Supplementing the diet of an equol producer with an equol enantiomer or mixture can provide benefits when the ordinary level of S-equol produced by the equol producer is inadequate because of 1) insufficient consumption of isoflavones to produce equol, 2) antibiotic use that ablates the activity of intestinal bacteria to make equol from precursor isoflavones, or 3) other health factors that impact the level of equol production, e.g. short bowel syndrome or surgical construction of an intestinal stoma such as ileostomy.
  • a supplemental level of equol is believed to provide enhanced effect on the health and well-being of the person.
  • This disclosure provides a method for delivering S-equol, R-equol, racemic equol, or non-racemic mixtures of equol, in sufficient amounts to have health benefits toward androgen-related diseases and conditions associated therewith.
  • the anti-androgenic activity of equol can affect a number of tissues throughout the body.
  • the blocking of androgenic activity of DHT can be beneficial for the treatment and prevention of: (A) growth of the prostate gland with aging, benign prostatic hyperplasia (BPH) and prostate cancer; (B) female- and male-pattern baldness, (C) facial and body hair growth (hirsutism), skin health (acne, anti-aging and anti-photo aging), skin integrity (collagen and elastin robustness); (D) body weight gain (and loss), reduction in adipose tissue deposition and metabolism of lipids, as well as general regulatory behaviors and effects, such as food and water intake, blood pressure changes, thyroid, glucose, leptin, insulin and the influence on the immune system; and (E) Alzheimer's disease and emotional, mental health issues, such as, mood, depression, anxiety and learning and memory by reducing the 5 ⁇ -steroid metabolites (covering androgens and progesterone) that are potent modulators of the GABA ⁇ receptor in the brain that influences all of the brain characteristics above.
  • the amount of composition comprising the equol is administered in an amount sufficient to produce a transient level of enantiomeric equol in the blood plasma of the mammal of at least 5 nanograms per milliliter (ng/mL), more typically at least 10 ng/mL or greater, or transient levels of enantiomeric equol in urine of greater than 1000 nmol/L.
  • the composition is administered orally in a dose amount of at least about 1 mg, more typically of at least 5 mg, and of up to 200 mg, more typically, up to 50 mg, of enantiomeric equol.
  • a typical level of bioavailability of R-Equol in plasma after oral administration of 20 mg of R-equol enantiomer to a healthy adult is shown in the appearance/disappearance plots of R-equol in FIGURE 2 .
  • R- and/or S-equol in sufficient amounts is believed to provide several advantages over delivery of a racemic mixture of equol.
  • the potency of R-equol or S-equol alone would typically be at least twice that of the racemic mixture.
  • the human body only produces the S-equol, and therefore, a composition comprising only S-equol represents a "natural" product with an ingredient, S-equol, with which the body is familiar.
  • a treatment composition comprising only, or substantially only, the R-enantiomer can produce beneficial and/or therapeutic effects.
  • administration of R-equol would supplement any endogenous S-equol present and allow for both estrogenic and anti-androgenic actions to occur in the body.
  • the disclosure includes the use of enantiomeric equol to treat and prevent diseases and conditions related to male- and female-pattern baldness.
  • DHT is a known cause of scalp hair loss.
  • An androgen, specifically the principal circulating androgen, testosterone, is converted to the more potent androgen, dihydrotestosterone (DHT) (in the hair follicle), and the hormonal action of DHT on scalp hair follicles cause hair loss.
  • DHT dihydrotestosterone
  • scalp hair loss can be decreased or prevented.
  • the disclosure includes the use of enantiomeric equol to treat and prevent diseases and conditions related facial and body hair. Facial and body hair are regulated by androgens, but oppositely to that of the regulation of scalp hair.
  • DHT more potent androgen
  • DHT increases facial and body hair.
  • DHT also increases the production of sebum (oil) from the sebaceous gland, which can contribute to an increase in acne.
  • the binding of DHT by equol can cause a decrease in facial and body hair and in secretion of sebum (oil), and a reduction or prevention of acne.
  • the disclosure includes the use of enantiomeric equol to treat and prevent diseases and conditions related to skin effects, skin quality and integrity, skin aging, skin photoaging, and skin pigmentation and lightening.
  • Estrogens before but especially after menopause, improve skin health by increasing elastin and collagen content to improve skin characteristics or robustness.
  • the repair mechanism is faster and the skin heals better if estrogen or estrogen-like compounds, such as equol, are present. It is believed that an equol enantiomer mixture, and particularly S-equol, is a good stimulator of elastin and collagen and also can protect against photo-aging.
  • Equol's blocking the hormone action of DHT can decrease sebum oil production from the sebaceous gland, which can decrease or eliminate acne. Since S-equol (though not R-equol) binds estrogen receptor(s) (mainly ER ⁇ ), the protective effects of this estrogen-like molecule would stimulate elastin and collagen in the skin. Additionally, since equol is a strong antioxidant, it can protect the skin from aging, including photo-aging.
  • the disclosure includes the use of enantiomeric equol to treat and prevent diseases and conditions related to improved prostate health.
  • the conversion of testosterone to the more potent androgen DHT is the result of the action of the enzyme 5 ⁇ -reductase within the prostate.
  • DHT causes benign prostatic hyperplasia (BPH), increases in the prostate weight, and can result in the need for prostatectomies and radiotherapy to treat these conditions.
  • BPH benign prostatic hyperplasia
  • increases in the prostate weight increases in the prostate weight, and can result in the need for prostatectomies and radiotherapy to treat these conditions.
  • consumption of soy foods has received increased attention due to their 'health benefits' of decreasing hormone dependent cancers such as prostate and breast cancer.
  • blockage of DHT by equol decreases prostate weight in animal models and presumably will block BPH to prevent prostate cancer.
  • the disclosure includes the use of enantiomeric equol to treat and prevent diseases and conditions related to brain function and mental health, including brain disorders, dementia of the Alzheimer type, as well as other reduced or impaired cognitive functions associated with advancing age and with short- and long-term memory loss.
  • Brain mechanisms are more complex, and attempting to define what molecules and factors regulate, influence, etc., mood, depression, anxiety and so on, can be difficult.
  • estrogens or estrogen-like molecules like isoflavones can assist cognitive function in conditions such as Alzheimer's disease, and may help to prevent the onset of such disorders, especially in postmenopausal women.
  • the second line of research is more complex and supports the view that 5 ⁇ -reduced steroids, especially progesterone, have the ability to bind GABA A receptors in the brain and cause sedation.
  • GABA A is the major inhibitory neurotransmitter in the brain and its receptors are abundant in brain areas that control mood/emotion.
  • individuals express less anxiety. For example, most women during pregnancy, report that they feel OK but they are usually tired or sleepy.
  • estrogen on the one hand decreases anxiety and hence increases activity. Conversely, blocking the action of 5 ⁇ -DHP also increases activity and thus in behavioral tests is interpreted as decreasing anxiety. For example, when the conversion of progesterone to 5 ⁇ - DHP in pregnant rats has been blocked, this results in a significant increase in their locomotor activity levels.
  • equol has the ability to bind 5 ⁇ -DHP (mainly seen in women) and 5 ⁇ -DHT (mainly seen in men). This would decrease the potent 'neurosteroid' effects at the GABA A receptor and decrease sedation and thus increase activity or decrease anxiety. Moreover, the ability of S-equol to bind the estrogen receptor(s) beta would also increase activity. Finally, our studies using young- or mid-aged adult rats, in males or females have shown that dietary phytoestrogen consumption ( Lund T.D. et al, Brain Res, 913:180-184 (2001 ); Lephart, E.D. et al, Neurotoxicology Teratology, 24:1-12 (2002 )), or injections with equol significantly decrease anxiety levels as expressed in the elevated plus maze test.
  • the elevated plus maze is a behavioral test used to quantify anxiety-related behavior and identify anxiolytic drugs ( Pellow S. et al, J eurosci Methods, 14:149-147 (1985 ); Current Protocols In Neuroscience (1997) 8.3.1- 8.3.15, John Wiley & Sons. NY, NY ).
  • the test relies on the inherent conflict between exploration of a novel environment and avoidance of its aversive features. Normally, animals spend little time and make few entries into the open arms of the maze compared to the closed arms of the maze ( Imhof J.T. et al, , Behav Brain Res, 56:177-180
  • the invention includes the use of enantiomeric equol to treat and prevent diseases and conditions related to body weight and body fat formation.
  • Phytoestogens including equol have the ability to decrease the formation of white adipose (fat) tissue and increase white adipose tissue breakdown, thus decreasing body weight. Also, the estrogen-like nature of phytoestrogen molecules decreases LDL (so-called "bad” cholesterol), blood pressure, and prevents insulin resistance (or in other words, provides beneficial effects to the diabetic condition). Since equol is a more potent isoflavone molecule compared to the other phytoestrogens, it presumably provides the health benefits and protects against the conditions outlined above.
  • equol Since equol binds DHT, equol can also block the actions of DHT that promote body weight gain. Thus, equol, and particularly S-equol, combined anti- androgenic but at the same time an estrogenic hormone action from the same molecule (equol) would further improve the health benefits of body weight loss (and weight management), decrease LDL cholesterol, decrease blood pressure, and help prevent the devastating effects of diabetes.
  • the disclosure includes the use of equol, as enantiomeric equol or mixture thereof, to treat and prevent lipid disorders such as high cholesterol (hypercholesterolemia), lipidemia, lipemia and dyslipidemia (disturbances in lipids).
  • lipid disorders such as high cholesterol (hypercholesterolemia), lipidemia, lipemia and dyslipidemia (disturbances in lipids).
  • the failure of soy protein to have significant cholesterol-lowering effects in adults with normal blood cholesterol levels, is, with few exceptions, probably because of heterogeneity in the study populations with regard to the metabolism of soy isoflavones and the failure to recognize the relevance of equol formation (and specifically, non-formation in non-equol producers).
  • the composition comprising equol is administered in an amount sufficient to reduce the level of
  • the disclosure further includes the use of R- and/or S-equol to improve diminished blood vessel quality, by increasing reactivity or flexibility in response to acute changes in blood pressure, improving blood flow, and reducing blood pressure.
  • the disclosure also includes the use of R- and/or S-equol to treat and prevent cancer, including benign prostate cancer, prostate cancer, and skin cancer.
  • Equol may also be used to prevent enlarged prostate or epididymis in individuals believed to be at risk for development of these pathologies, without alterations in testes, pituitary or body weights.
  • the equol may be administered by any route that allows absorption of equol to the blood stream.
  • equol as a diagnostic agent in androgen-related disorders as well as disorders arising from disturbances in estrogenic/androgenic balance.
  • equol is administered to an individual to bind DHT and thereby prevent DHT binding to androgen receptors.
  • the changes in estrogenic balance are then measured or the change in androgen-binding is assessed to diagnose or further elucidate androgen- related anomalies.
  • Equol can be administered to bind DHT prior to or along with other therapeutic moieties in order to assess the binding capacity of DHT with respect to the therapeutic moiety in question.
  • androgen-binding moieties can be administered following administration of equol to assess the efficacy of the androgen-binding moiety to restore androgen activity and balance estrogenic activity in the absence of DHT binding.
  • equol can be administered in the presence of DHT-binding moieties in order to displace these naturally-occurring or xenobiotic DHT-binding moieties from DHT.
  • the equol may be administered by supplying an oral dosage form of equol to either an "equol-producing" mammal or a "non-equol producing” mammal, or an oral dosage of daidzein, daidzin, isoflavone mixtures containing daidzein, or soy protein preparations to an "equol-producing" mammal, wherein the administration of the oral dosage form results in effective absorption of equol to the blood stream.
  • Administration of equol may be made by routes other than oral if desired.
  • rectal or urethral administration may be used to administer equol for the treatment of enlarged prostate or to prevent prostate enlargement.
  • the active ligand binding site of the equol molecule may be isolated and synthesized for administration, which can provide DHT binding without the full equol molecule.
  • the dose of the equol molecule or fragment thereof having DHT-binding abilities is dependent upon the route of administration and the condition to be treated. Based on our in vivo studies it is apparent that relatively low doses of equol antagonize much higher doses of DHT, and this may be explained by the marked differences in the binding of equol to serum protein compared with DHT.
  • the dose may be increased dramatically without incurring significant dose-limiting side effects to greater than about 10mg/kg.
  • Oral administration can be effected in microencapsulated forms that can provide delayed or sustained release of the medicament.
  • Equol can be administered topically, transdermally, and subdermally in a variety of forms, including lotions, ointments, foams (including shaving creams), nasal sprays, skin patches (such as described in US Patent 5,613,958 ,), electromechanical devices, including micropumps systems (such as described in US Patent 5,693,018 and US Patent 5,848,991 ), and subdermal implants (such as described in US Patent 5,468,501 ).
  • Equol was isolated from urine (25 mL) by passage of the sample through a solid -phase Bond Elut C18 cartridge. After washing the cartridge with water, the isoflavones were recovered by elution with methanol (5 mL) and the methanolic phase was taken to dryness under a stream of nitrogen. The sample was subjected to enzymatic hydrolysis with Helix pomatia and then re-extracted on a Bond Elut C18 cartridge. The methanolic extract was taken to dryness under nitrogen gas and redissolved in HPLC mobile phase (100 ⁇ L).
  • Equol enantiomers were identified by HPLC using a Chiralcel OJ chiral phase column as described herein above. The detection of equol was achieved by selected ion monitoring electrospray ionization mass spectrometry (ESI-MS). Mass chromatograms of a pure standard of S-equol, and of urine from an adult consuming soy food are shown in FIGURE 3 . Similar studies have demonstrated that soy-derived isoflavones are converted to equol in rats, as well, thus validating rodent models of isoflavone metabolism.
  • ESI-MS electrospray ionization mass spectrometry
  • the retention index and mass chromatogram establish that it is exclusively the S-enantiomer of equol that is excreted in human urine as no detectable R-enantiomer of equol could be found. Analysis of the plasma from the same 'equol-producer' also revealed only the S-enantiomer of equol.
  • Daidzein (200 mg, 0.8 mmol) is dissolved in a mixture of glacial acetic acid (20 mL) and isopropanol (20 mL), and is reduced with 10% Pd on charcoal (150 mg) at 55 p.s.i.g. (3.7 atm gauge).
  • Pd on charcoal 150 mg
  • the catalyst is filtered off, and the filtrate is evaporated.
  • FIGURE 4 shows the GC-MS analysis of the trimethylsilyl ether derivative of synthesized product as a single pure peak and a mass spectrum that is consistent with the published electron ionization spectrum of the trimethylsilyl (TMS) ether derivative of authentic equol.
  • the molecular ion as expected is at m/z 470 and the base peak at m/z 234.
  • the purified equol product had a purity of greater than 99%, as confirmed by HPLC and mass spectrometry.
  • a racemic mixture of S-equol and R-equol were separated by chiral chromatography on a Chiralcel OJ Column using a flow-rate of 1.0 mL/min and with a gradient elution consisting of an initial mobile phase of 10% ethanol in hexane and increasing to 90% ethanol in hexane over a time period of 15 minutes according to the program shown in Table 1: Table 1: Chiral separation gradient eluent of hexane and ethanol Time (min.) % hexane % ethanol 0 90 10 1.0 90 10 15.0 10 90 16.0 90 10 17.0 90 10
  • FIGURE 5 shows the mass chromatogram of the ions recording (m/z 241) for a racemic mixture of S- and R-equol.
  • Enantiomer-1 material (1.6 mg exact weight) had first and second measurements of -0.023 and -0.022, resulting in an optical rotation of -14 [-0.0225 x 1000/1.6], which corresponds with the S-enantiomer of equol.
  • Enantiomer-2 material (1.7 mg exact weight) had first and second measurements of + 0.023 and + 0.023, resulting in an optical rotation of+ 13.5 [+ 0.023 x 1000/1.7], which corresponds with the R-enantiomer of equol.
  • Hormone Receptor Proteins Full length rat ER ⁇ expression vector (pcDNA-ER ⁇ ; RH Price UCSF) and ER ⁇ expression vector (pcDNA-ER ⁇ ; TA Brown, Pfizer, Groton, CT) were used to synthesize hormone receptors in vitro using the TnT-coupled reticulocyte lysate system (Promega, Madison, WI) with T7-RNA polymerase, during a 90 min reaction at 30° C. Translation reaction mixtures were stored at -80° C until further use.
  • mice are given subcutaneous (sc) injections (1/day for 4 days) of either dimethylsulfoxide (DMSO) (vehicle control) or racemic equol (0.25 mg/kg). Eighteen hours after the final injection, animals are killed via decapitation and trunk blood and prostate are collected for analysis.
  • DMSO dimethylsulfoxide
  • equol In addition to equol's effects on prostate racemic equol blocks the effects of DHT in other tissues, and decreases body weight.
  • DMSO control
  • equol 0.5 mg/kg
  • Rats injected with R-equol have a significant decrease in body weight gain compared to control rats, as shown in Table 3.
  • Table 3 Body Weight Gained in Male Sprague-Dawley Rats Treated with Equol.
  • Testis and pituitary gland weights are not significantly altered by the treatments (data not shown).
  • the slight decreases in body weight (around 10 %) from the equol experiments are very similar to those seen between animals fed a Phyto-Free diet (a diet containing very low levels of phytoestrogens) vs. a Phyto-600 diet (a phytoestrogen-rich diet containing 600 ppm of isoflavones).
  • the significant reduction in white adipose tissue deposition with the racemic equol injections (around 36 %) is also comparable with that seen with the data sets derived from the dietary treatment studies.
  • This example demonstrates the effects of racemic equol on androgen-sensitive tissues.
  • animals are gonadectomized (GDX) under isoflurane anesthesia and allowed to recover for 7 days.
  • animals are assigned to the following groups 1) DMSO, 2) DHTP (2mg/kg), 3) racemic equol (0.25 mg/kg), or 4) both DHTP and racemic equol.
  • Injections are given subcutaneously daily for 4 days. Animals are killed via decapitation and trunk blood and tissues are collected for analysis. Plasma DHT is measured, shown in FIGURE 11 .
  • Plasma DHT was further elevated, although, not significantly, by co-treatment with equol.
  • Tissues including prostate, testes and epididymis, are removed from the animal, dissected free of fat and connective tissues, weighed, fixed by immersion in 4% paraformaldehyde, and then sectioned at 15 ⁇ m on a cryostat. Tissue sections are mounted on charged slides (Superfrost Plus, Fisher Scientific, Pittsburgh, PA) prewarmed to 23° C, and stained with hematoxylin and eosin (H&E), dehydrated in ascending alcohol and cleared with xylene.
  • H&E hematoxylin and eosin
  • FIGURES 12 and 13 Histological sections are shown in FIGURES 12 and 13 .
  • H&E stained prostates reflect a change due to both GDX and treatments.
  • the prostate glands of control, equol, and DHTP plus equol treated groups show similar histology ( Figure 12 A, B, D).
  • prostates are characterized by very small atrophic glands with little volume in the gland lumen.
  • DHTP-treated animals Figure 12 C
  • the glands show signs of cell proliferation. Lumen size is increased compared to GDX animals; the epithelium is of a tall columnar type ( Figure 12 C) .
  • Adipose tissue (dissected from just below the kidneys to just above the testes in the abdominopelvic cavity) is measured in the 55 or 75 day-old males. At both ages, white adipose tissue mass is significantly greater in the Phyto-Free-fed males compared to Phyto-600-fed animals, FIGURE 15 . It should be noted that the reductions in body weight of Phyto-600-fed males are modest, at approximately 10 to 15% percent, whereas, the reductions in white adipose tissue from the same animals are approximately 50-60% compared to Phyto-Free-fed males.
  • leptin is produced by adipose tissue ( D.A. Sandoval et al., J Diabetes Complications, 2003, 17:108-113 .), serum leptin levels are measured, along with insulin levels, to determine the alterations in these metabolic hormones.
  • leptin levels at 33, 55 or 75 days of age are significantly decreased in Phyto-600-fed males (which corresponds with the reductions seen in adipose tissue weights from these same animals) compared to Phyto-Free-fed males.
  • insulin levels are significantly decreased in Phyto-600-fed male vs. Phyto-Free-fed males ( FIGURE 17B ), consistent with the benefits of protecting against insulin resistance associated with type-2 diabetes ( V. Jayagopal et al., Diabetes Care, 2002, 25:1709-1714 .).
  • T3 serum glucose and thyroid
  • mice fed the Phyto-600 diet display significantly lower body weights at 80 days of age compared to animals fed the Phyto-Free diet, representing about a 12 % reduction in body weight in the Phyto-600-fed animals.
  • females fed the Phyto-600 diet also displayed significant reductions in adipose tissue weight (by about 68 %) compared to females fed the Phyto-Free diet, shown in FIGURE 21 .
  • OVX ovariectomized rats.
  • the OVX rat is a well-established animal model of postmenopausal human females.
  • OVX permits the subcutaneous injections of estrogen and progesterone to stimulate behavioral estrus in rats, to determine the effects of a Phyto-600 or Phyto-Free diet.
  • Adult ovariectomized rats are fed a phytoestrogen diet of approximately 200 ppm of isoflavones ("Phyto-200”) until 50 days of age (all animals are ovariectomized at approximately 40 days of age).
  • the female rats are age and weight matched at 50 days of age and placed into one of two diet treatments: either the Phyto-600 (black bars) or Phyto-Free (white bars) until 94 days of age.
  • Baseline body weights are taken at 50 days of age before the animals are placed on the diet treatments, again at 58 days (8 days of diet treatment), at 92 days of age (before injection of estradiol), and at 94 days of age (before injection of progesterone, and 6 hours later at 94 days of age (after chemical induction of behavioral estrus), shown in FIGURE 28 .
  • the Phyto-600-fed rats After consuming the diets for 8 days, the Phyto-600-fed rats display a slight but significant reduction in body weight (of about 7%) compared to Phyto-Free-fed. This reduction in body weight is maintained before and during the chemical induction of behavioral estrus by the estrogen and progesterone (steroid) injections.
  • White adipose tissue is measured at 94 days of age after the chemical induction of behavioral estrus, Phyto-600-fed OVX rats have approximately 50% less white adipose tissue mass compared to Phyto-Free-fed OVX rats, shown in FIGURE 29 , consistent with findings in Examples 9 and 10.
  • Serum leptin levels in Phyto-600-fed OVX rats are decreased by approximately 30 % compared to Phyto-Free-fed rats, shown in FIGURE 30 , reflecting the decreased white adipose tissue mass.
  • Male and female Long-Evans rats are purchased from a supplier at 50 days of age. All animals are raised (from conception to 50 days of age) on the Phyto-200 diet. At 50 days old the male and female rats are randomly assigned to one of four diet treatment groups: 1) AIN-76 diet containing approximately ⁇ 5 ppm isoflavones, 2) the Phyto-Free, 3) Phyto-200, or 4) Phyto-600 diet, described in previous examples.
  • the AIN-76 diet contains extremely low concentrations of isoflavones, its formulation is quite different compared to the other three diets.
  • the sucrose content is very high (almost approaching 50% of the total diet formulation) and has a dense white consistency that the rats may not enjoy consuming as much as the regular plant-based ingredient diets (i.e., the Phyto-Free diet uses corn and wheat in its formulation which contains very low levels of isoflavones); the Phyto-200 or Phyto-600 diets use varying amount of soy meal in their formulations.
  • the male rats are maintained on their assigned diets until 350 days of age (equivalent to middle-age in humans).
  • the female rats are maintained on the diets until 279 days of age (approaching middle-age in humans). Food and water intake is measured to determine the potential influence of these parameters on body weight changes. In each case these factors do not contribute to the reductions in body weight with consumption of the isoflavone-containing diets (i.e., Phyto-200 and Phyto-600 diets; data not shown).
  • FIGURE 31 body weights are recorded, shown in FIGURE 31 .
  • the males fed the Phyto-Free diet have the heaviest body weights and the Phyto-600-fed males have the lowest, while the males on the AIN-76 and the Phyto-200 diets fall in between these two group values.
  • the Phyto-600-fed body weights are significantly lower, by approximately 14%, than the Phyto-Free-Fed males.
  • the male rats have a similar profile to that observed at 112 days of age, shown in FIGURES 32 and 33 , respectively.
  • the males fed the Phyto-Free diet display the heaviest body weights and the Phyto-600-fed males display the lowest body weights, while the males on the AIN-76 and Phyto-200 diets fall in between these two group values.
  • Males fed the AIN-76 or the Phyto-Phyto-Free fed males display the highest white adipose tissue weights, measured at 350 days of age.
  • the Phyto-200-fed males show a 19 % non-significant reduction in white adipose tissue weight compared to AIN-76 or Phyto-Free-fed rats.
  • Male rats fed the Phyto-600 diet have significantly less adipose tissue mass, an approximate 40 % reduction, compared to AIN-76 or Phyto-Free-fed rats, shown in FIGURE 34 .
  • Both serum insulin and leptin levels are significantly reduced as a function of increasing concentrations of isoflavones in the diet treatments, shown in FIGURES 35 and 36 , respectively.
  • males fed the Phyto-200 or Phyto-600 diets have significant reductions in insulin levels compared to AIN-76 fed males.
  • Phyto-600-fed males show an approximate 50% reduction in insulin levels compared to Phyto-Free-fed male Serum leptin profiles display a similar pattern to that of the insulin results, where Phyto-200- or Phyto-600-fed males have significant reductions in serum insulin levels compared to either AIN-76 or Phyto-Free-fed males.
  • Insulin levels in the Phyto-600-fed males are 46 % lower compared to the Phyto-200-fed males. However, the difference between these two diet groups do not reach significance (p ⁇ 0.065).
  • the body weights are measured at 112 and 279 days of age.
  • females fed the Phyto-Free and the Phyto-200 diets have the heaviest body weights and the Phyto-600-fed females have the lowest, while the AIN-76 diet group fall in between the values of the other three groups, shown in FIGURE 37 .
  • Body weights of the Phyto-600-fed groups are significantly lower, by approximately 10%, compared to the Phyto-Free- and the Phyto-200-fed females.
  • female rats have a similar profile to that of age-matched males for changes in body weight as influenced by the diet treatments, shown in FIGURE 38 .
  • Females fed the Phyto-600 diet display the lowest body weights compared to AIN-76 or Phyto-Free-fed groups. This significant reduction in body weight in Phyto-600-fed females is approximately 15% between the diet treatment groups tested.
  • Noble rats were used to determine whether an inbred strain of rat has body and adipose tissue changes similar to those of out-bred strains of rats such as the Long-Evans animals when placed on isoflavone-rich diets. Due to inbreeding, Noble rats are more fragile animals. For example, pregnant dams do not always carry their litters to term and frequently have smaller litters. Noble rats have been used for more than twenty years because they spontaneously generate tumors with aging, especially in hormonal-dependent organs of the reproductive tract. Thus, Noble rats have been extensively studied in the area of cancer research (e.g., R.L. Noble, Prostate carcinoma of the Nb rat in relation to hormones, Int Rev Exp Pathol, 1982, 23:113-159 ).
  • Male and female Noble rats are fed either the Phyto-Free or Phyto-600 diets from conception until 145 days of age.
  • Male Noble rats fed the Phyto-600 diet have significantly lower body weights at 145 days of age compared to age-matched males fed the Phyto-Free diet, shown in FIGURE 39 .
  • the significant reduction in body weight represents a modest but consistent decrease of approximately 8 % compared to Phyto-Free-fed males.
  • white adipose tissue mass is significantly decreased in Phyto-600-fed males compared to Phyto-Free-fed, shown in FIGURE 40 .
  • Female Noble rats fed the Phyto-600 diet have a 6% reduction in body weight compared to Phyto-Free-fed females, shown in FIGURE 41 .
  • White adipose tissue mass is markedly decreased female Noble rats fed the Phyto-600 diet, shown in FIGURE 42 .
  • the Phyto-600 diet group has a 61 % reduction in adipose tissue compared to Phyto-Free- fed rats. The decrease in white adipose tissue is similar to that seen in Long-Evans rats.
  • Phyto-Free diet Prior to initiation of a Phyto-Free diet period Male Long-Evans rats are fed a Phyto-200 diet, as described in previous examples. The rats are placed on a diet containing the Phyto-Free diet at approximately 52 days of age and randomly assigned to three groups. Baseline body weights after 14 days and 21 days on the Phyto-Free diet for all rats are similar, shown in FIGURES 43 and 44 , respectively.
  • rats receive daily subcutaneous 0.1cc injections of vehicle (peanut oil), 1 milligram of a racemic mixture of equol in vehicle (0.83 mg/kg body weight/day), or 5 milligrams of a racemic mixture of equol in vehicle (4.2 mg/kg body weight/day) once every three days.
  • vehicle peanut oil
  • 1 milligram of a racemic mixture of equol in vehicle (0.83 mg/kg body weight/day)
  • 5 milligrams of a racemic mixture of equol in vehicle 4.2 mg/kg body weight/day
  • testis weights are quantified in these animals. There are no significant alterations in testes weight with the equol injections, with testicular weight essentially the same among the injection treatment groups, shown in FIGURE 50 .
  • serum phytoestrogen levels are quantified by GC/MS according to the method described by Coward L et al, J Agric Food Chem, 41:1961-1967 .
  • the behavioral patterns of anxiety are compared to the serum profiles of circulating isoflavone levels in the diet treatment groups by sex.
  • the serum phytoestrogen levels are determined and compared to the patterns of anxiety-related behaviors.
  • the circulating isoflavone levels correspond to the expression of anxiety-related behaviors, demonstrating an association between circulating isoflavone molecules and anxiety.

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Claims (9)

  1. Utilisation d'un énantiomère de R-équol ou d'un mélange non racémique d'énantiomères de R-équol et de S-équol à un rapport de S-équol à R-équol inférieur à 50:50 à 1:99,5 dans la fabrication d'un médicament pour le traitement d'une condition pathophysiologique médiée par les androgènes chez un mammifère, où ladite condition pathophysiologique est choisie parmi l'obésité ou la prise de poids corporel.
  2. Utilisation selon la revendication 1, où ledit médicament est une composition orale comprenant au moins 1 mg d'équol.
  3. Utilisation selon la revendication 1, où ledit médicament est une composition topique comprenant au moins 0,1 % d'équol.
  4. Utilisation selon la revendication 3, où ledit médicament ne comprend pas une quantité significative d'un quelconque autre composé de liaison au récepteur des androgènes.
  5. Énantiomère de R-équol ou mélange non racémique d'énantiomères de R-équol et de S-équol à un rapport de S-équol à R-équol inférieur à 50:50 à 1:99,5 pour une utilisation dans un procédé de traitement d'une condition pathophysiologique médiée par les androgènes chez un mammifère, où ladite condition pathophysiologique est choisie parmi l'obésité ou la prise de poids corporel.
  6. Énantiomère de R-équol ou mélange non racémique d'énantiomères de R-équol et de S-équol pour une utilisation selon la revendication 5 qui se présentent sous la forme d'une composition orale comprenant au moins 1 mg d'équol.
  7. Énantiomère de R-équol ou mélange non racémique d'énantiomères de R-équol et de S-équol pour une utilisation selon la revendication 5 qui se présentent sous la forme d'une composition topique comprenant au moins 0,1 % d'équol.
  8. Énantiomère de R-équol ou mélange non racémique d'énantiomères de R-équol et de S-équol pour une utilisation selon la revendication 7 qui sont présents dans une composition qui ne comprend pas une quantité significative d'un quelconque autre composé de liaison au récepteur des androgènes.
  9. Dosage par liaison compétitive pour déterminer la présence d'un fragment de liaison aux androgènes, à l'exclusion des procédés de diagnostic pratiqués sur le corps d'humains ou d'animaux, ledit dosage comprenant les étapes consistant à :
    1) fournir un récepteur des androgènes,
    2) fournir un complexe de DHT-équol,
    3) fournir une substance de test comprenant un fragment de liaison aux androgènes, et
    4) mettre en contact le récepteur des androgènes et la substance de test avec le complexe de DHT-équol et effectuer le dosage par liaison compétitive.
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US9408825B2 (en) 2016-08-09
AU2003286781A1 (en) 2004-05-25
WO2004039327A3 (fr) 2004-10-07
AU2003286781B2 (en) 2009-05-21
US20180185326A1 (en) 2018-07-05
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US20100087519A1 (en) 2010-04-08
US9889116B2 (en) 2018-02-13
US20160256436A1 (en) 2016-09-08
US9089547B2 (en) 2015-07-28
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US20150342924A1 (en) 2015-12-03
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US8153684B2 (en) 2012-04-10
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US10111855B2 (en) 2018-10-30
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US20120264821A1 (en) 2012-10-18
US20140135387A1 (en) 2014-05-15
EP1569636A2 (fr) 2005-09-07
CA2504682A1 (fr) 2004-05-13

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